The current obesity epidemic in the US is the major contributor to the soaring rates of metabolic diseases and to skyrocketing health care costs. Yet the molecular and pathological mechanisms by which obesity induces metabolic disorders remain incompletely understood, and therapeutic interventions for obesity and related metabolic abnormalities are limited. In recent years, tens of thousands of long non-coding RNAs lncRNAs (lncRNAs) have been identified to constitute a significant portion of the human genome and play a diverse role in biological processes. However, majority of human lncRNAs are human- or primate-specific and their relevance to diseases cannot be directly studied in any of the existing experimental systems. To systemically analyze the role of lncRNAs in human disease, we develop an experimental pipeline to identify and functionally annotate human lncRNAs that are regulated by GWAS loci of major metabolic diseases. We first perform bioinformatic analyses to identify all lncRNAs that are regulated by GWAS loci that predispose an individual to metabolic diseases. We then infer the function of these lncRNAs based on the molecular pathways they correlate with and their expression regulation in vivo. Finally, we experimentally interrogate the function of these disease-associated lncRNAs using a humanized mouse model in which the liver is populated with human hepatocytes. Our work provides a fully integrated experimental pipeline to study the pathological role of human-specific lncRNAs in metabolic disorders and also establishes a framework that can be broadly adapted to uncover lncRNA-mediated mechanisms of most common human diseases.